Narrative review
Deep vein thrombosis: update on diagnosis and
MJA 210 (11) ▪ 17 June 2019
516
management
Paul C Kruger 1,2,3, John W Eikelboom3,4, James D Douketis 4,5, Graeme J Hankey6
V
enous thromboembolism (VTE) most commonly man-
ifests as lower extremity deep vein thrombosis (DVT)
and pulmonary embolism and has an annual incidence
of 1–2 per 1000 population.1 Mortality is high; death within
30 days occurs in about 6% of patients with DVT, primarily
through pulmonary embolism, and in 13% of patients with
pulmonary embolism.2 Among treated patients, about 20–50%
develop post-­t hrombotic syndrome (PTS) after DVT, and 3% de-
velop chronic thromboembolic pulmonary hypertension after
pulmonary embolism.3,4 After 3–6 months of anticoagulation,
VTE recurs in up to 40% of patients within 10 years. The risk of
recurrence is two-­to threefold higher after unprovoked than
provoked VTE.5,6
In the past decade, there have been notable advances in risk pre-
diction, diagnosis and treatment with direct oral anticoagulants
(DOACs), thrombolysis and catheters. Nevertheless, there re-
mains uncertainty about the optimal duration of anticoagulation
after unprovoked VTE, indications for thrombophilia screening,
and the role of catheter-­directed thrombolysis.7
This review summarises contemporary evidence on the diag-
nosis and management of DVT. We searched PubMed for rele-
vant articles, from 1996 to 2019, using the search terms “venous
thromboembolism”, “deep vein thrombosis”, “pulmonary em-
bolism”, “thrombosis”, “anticoagulant” and “anticoagulation”.
An accompanying article addresses pulmonary embolism.8
Guidelines from the Thrombosis and Haemostasis Society of
Australia and New Zealand (THANZ) underpin evidenced-­
based recommendations,9 which have been graded according
to the National Health and Medical Research Council levels of
evidence (Box 1).10
Diagnosis
The clinical presentation of DVT is often non-­specific. Hence,
accurate diagnosis requires sequential integration of clinical
features, assessment of pre-­test clinical probability, and confirm-
atory investigations that include D-­dimer testing and imaging.
Symptoms and signs of deep vein thrombosis
Symptoms and signs of leg or pelvis DVT include leg pain,
swelling, erythema and dilated superficial veins. Arm DVT has
similar symptoms localised to the arm. Some DVTs are asymp-
tomatic. Differential diagnoses for limb DVT include cellulitis,
lymphoedema, chronic venous insufficiency, haematoma and,
for leg DVT, ruptured Baker cyst.11
Pre-­test clinical gestalt or impression
The gestalt probability of DVT is an unstructured impression of
the likelihood of DVT based on clinical assessment. It can help
determine the pre-­test probability of DVT when it is estimated
by an experienced physician.12,13 However, validated clinical de-
cision rules are more reliable.14
1
Fiona Stanley Hospital, Perth, WA. 2 PathWest Laboratory Medicine, Perth, WA. 3 Population Health Research Institute, Hamilton, Canada. 4 Hamilton Health Sciences, Hamilton, Canada.
5
St. Joseph’s Healthcare Hamilton, McMaster University, Hamilton, Canada. 6 University of Western Australia, Perth, WA.
Podcast with Paul Kruger available at https://www.mja.com.au/podcasts
Summary
• Diagnosis of deep vein thrombosis (DVT) requires a multifaceted
approach that includes clinical assessment, evaluation of pre-test
probability, and objective diagnostic testing.
• Common symptoms and signs of DVT are pain, swelling, ery-
thema and dilated veins in the affected limb.
• The pre-test probability of DVT can be assessed using a clinical
decision rule that stratifies DVT into “unlikely” or “likely”. If DVT
is “unlikely”, refer for D-dimer test. If the D-dimer level is normal,
DVT can be excluded; if the D-dimer level is increased, refer for
compression ultrasound. If DVT is “likely”, refer for compression
ultrasound.
• When DVT is confirmed, anticoagulation is indicated to control
symptoms, prevent progression and reduce the risk of post-
thrombotic syndrome and pulmonary embolism.
• Anticoagulation may consist of a parenteral anticoagulant over-
lapped by warfarin or followed by a direct oral anticoagulant
(DOAC) (dabigatran or edoxaban), or of a DOAC (apixaban or ri-
varoxaban) without initial parenteral therapy.
• DOACs are the preferred treatment for DVT because they are
at least as effective, safer and more convenient than warfarin.
DOACs may require dose reduction or avoidance in patients with
renal dysfunction, and should be avoided in pregnancy.
• Recent evidence shows that DVT in patients with cancer may be
treated with edoxaban (after discontinuation of 5 days of initial
heparin or low molecular weight heparin [LMWH]) or rivaroxaban
if patients prefer not to have daily injections of LMWH, but the
risk of gastrointestinal bleeding is higher with DOACs than with
LMWH in patients with gastrointestinal cancer.
Pre-­test probability using a clinical decision rule
In primary care and in outpatients with suspected DVT, the
Wells rule for DVT helps calculate the pre-­test probability of
DVT and guide investigations.9 The Wells rule assigns points for
clinical symptoms and risk factors for DVT to produce a total
score between −2 and 9 points, which stratifies patients as “un-
likely” (≤ 1 point) or “likely” (≥ 2 points) to have DVT.15 A poten-
tial weakness is the need for clinicians to subjectively determine
whether an alternative (non-­DVT) diagnosis is likely or unlikely,
as both groups require investigations.
Among inpatients with suspected DVT, imaging is required
because clinical decision rules have not been validated and
­D-­dimer testing has a high frequency of false positive results.
D-­dimer testing
D-­dimer levels are raised in most patients with DVT (sensi-
tivity, 94–96%) and also in older patients and in patients with
malignancy, sepsis, inflammation, chronic kidney failure, re-
cent surgery, trauma, severe burns, and pregnancy (specificity,
42–52%).16,17 Therefore, a negative D-­dimer result helps exclude
DVT, particularly when the clinical probability is low, and a pos-
itive D-­dimer result requires imaging to confirm DVT.
graeme.hankey@uwa.edu.au ▪ doi: 10.5694/mja2.50201
 Narrative review

1  The National Health and Medical Research Council levels of 2  Diagnosing first deep vein thrombosis (DVT) presenting in an
evidence10 outpatient or in primary care
Evidence
Component base Definition

A Excellent One or more level I studies with a

low risk of bias or several level II
studies with a low risk of bias

B Good One or two level II studies with a low

risk of bias or a systematic review
or several level III studies with a low
risk of bias

C Satisfactory One or two level III studies with a

low risk of bias, or level I or II studies
with a moderate risk of bias

D Poor Level IV studies, or level I to III stud-

ies or systematic reviews with a high
risk of bias

D-­dimer testing may also be used to predict the risk of recurrent

VTE after ceasing anticoagulation, but is not recommended as CUS = compression ultrasound. ◆
a screening test for subclinical disease recurrence or to monitor
response to anticoagulation.18

Diagnostic imaging
Venous compression ultrasound (CUS) is the first-­line imaging
test for suspected DVT.19 There are two acceptable strategies. The
first is CUS limited to the proximal leg (thigh and popliteal re-
gion) to diagnose proximal DVT, and to repeat one week later to
assess for distal DVT extending proximally. The second is CUS
of the whole leg which, if negative, avoids the need for a repeat
limited CUS, but may diagnose distal DVTs that may not require
anticoagulation.20 The risk of missing a DVT in the first 3 months
after a negative whole leg CUS is less than 2%.21 Compared with
venography, CUS has a sensitivity of 93.8% (95% CI, 92.0–95.3)
and specificity of 97.8% (95% CI, 97.0–98.4) for proximal DVT.22
probability of DVT because a negative D-­dimer result does not
exclude DVT with sufficient certainty in such patients, and an
increased D-­dimer level is not specific for DVT.18,23
Investigating for underlying risk factors
Risk factors for DVT (Box 3) determine the risk of recurrent
DVT.25
Unprovoked VTE requires assessment for occult cancer, present
in up to 10% of patients.26 However, extensive cancer screening
with computed tomography of the body or tumour markers
is not recommended, unless symptoms of possible cancer are
present.27

Using an integrated approach to diagnosis of first deep vein
thrombosis
The diagnosis of DVT requires an integrated approach because
the clinical presentation, clinical decision rule or investigations
used in isolation may be insufficient to confirm or exclude DVT
(Box 2). Alternative algorithms have been presented by the
American Society of Hematology and THANZ.9,14
A low to moderate pre-­test probability by gestalt, or “unlikely”
DVT (Wells rule ≤ 1), indicates the need for D-­dimer measurement.
D-­dimer has a negative predictive value of 99.1% (95% CI, 96.7–
99.9) in populations with a 16% prevalence of DVT.23 Therefore, a
normal D-­dimer level in patients with “unlikely” DVT effectively
excludes DVT (evidence level A; Box 1). An increased D-­dimer
level infers that DVT may be present (along with other alternative
Testing for hereditary thrombophilia may identify predisposi-
tion to the development of VTE, guide testing of family members,
and determine the need for long term prophylactic anticoagula-
tion. However, thrombophilia testing is not indicated routinely.
Selecting who to test requires consideration because the results
will not change management in most patients with VTE, as the
most common thrombophilias (factor V Leiden and prothrom-
bin gene mutations) are not strong predictors of recurrent VTE.28
Testing for thrombophilia can be considered in patients with un-
provoked VTE who are aged less than 50 years, or who have a
strong family history of VTE, or who have recurrent venous or
arterial thrombosis.29,30 Thrombophilia testing should not be
performed in patients with VTE provoked by surgery or major
trauma (evidence level B) because the risk of recurrent VTE is low.
Testing for the antiphospholipid syndrome — an acquired
MJA 210 (11) ▪ 17 June 2019

diagnoses) and indicates the need for a CUS to confirm or exclude

DVT. A CUS that is positive for proximal DVT confirms DVT and
the need to initiate anticoagulant therapy, whereas anticoagulant
therapy can be withheld with a negative CUS. Ideally, a negative
above-­knee CUS should be repeated one week later to exclude
the presence of a distal DVT that may have extended proximally.
Alternatively, a whole-­leg CUS may be performed and, if negative
for DVT, does not need to be repeated (evidence level A).24
A high pre-­test probability by gestalt, or “likely” DVT (Wells
rule ≥ 2), indicates CUS, without the need for D-­dimer testing.
D-­dimer should not be measured in patients with a high pre-­test
thrombophilia — is indicated when patients develop arterial or
venous thrombosis in the setting of thrombocytopenia, haemo-
lytic anaemia, livedo reticularis or cognitive dysfunction in the
absence of a stroke.31 Patients with abdominal (portal or hepatic
vein) thrombosis may have an underlying myeloproliferative
disorder, and Janus kinase 2 (JAK2) V617F mutation testing is
recommended in patients without cirrhosis or malignancy.32
When DVT occurs in the setting of pancytopenia or haemolytic
anaemia, testing for paroxysmal nocturnal haemoglobinuria
should be considered, especially if the DVT is in an unusual 517
­location (eg, splanchnic veins or cerebral sinuses).33,34
 Narrative review

3  Risk factors for venous thromboembolism* 25

VTE risk factor category Examples

Transient • Major: surgery with general anaesthesia > 30 minutes, confined to bed in hospital ≥ 3 days with an
acute illness, or caesarean section
• Minor: surgery with general anaesthesia < 30 minutes, admission to hospital < 3 days with an acute
illness, oestrogen therapy, pregnancy, confined to bed out of hospital for ≥ 3 days with an acute illness,
leg injury with reduced mobility

Permanent/persistent • Active cancer

• Chronic inflammation (eg, inflammatory bowel disease)
• Chronic autoimmune disease
• Chronic infections

Unprovoked • No transient or permanent/persistent factors

Non-­environmental • Male
• Hereditary thrombophilia (eg, protein C deficiency, protein S deficiency, antithrombin deficiency, factor
V Leiden mutation, prothrombin gene mutation)
• Older age

* Environmental (or acquired) risk factors for venous thromboembolism (VTE) may be transient or persistent. A transient risk factor is one that resolves after it has provoked the VTE.
Resolution of the transient risk factor should be confirmed before stopping anticoagulation therapy. A permanent/persistent risk factor is one that is still present after it provokes the VTE. A
VTE that occurs without transient or permanent/persistent risk factors is considered unprovoked. Non-­environmental (or intrinsic) risk factors do not influence whether a VTE is considered
provoked or unprovoked but may influence the risk of recurrence. ◆

exceed 100 mg daily, but, otherwise, it should be avoided during

Investigating patients with deep vein thrombosis for
simultaneous pulmonary embolism
About 56% of patients with proximal DVT have pulmonary em-
bolism.35 Chest imaging is not needed routinely because anti-
coagulation is required regardless, but it may be justified if the
patient has significant symptoms of pulmonary embolism, as
this may change management (eg, thrombolysis for clinically
massive pulmonary embolism) and prognosis (eg, long term risk
of chronic thromboembolic pulmonary hypertension).8
Management
Anticoagulation
Anticoagulation is the mainstay of treatment for VTE; it aims to
reduce mortality, thrombus extension, recurrence, and the risk
of PTS (after DVT) and chronic thromboembolic pulmonary hy-
pertension (after pulmonary embolism). The phases of antico-
agulation treatment are “initial” (first week after VTE diagnosis),
“long term” (first 3 months after diagnosis) and “extended” (no
scheduled stop date) (Box 4).36
Clinically significant bleeding is a contraindication to anticoag-
ulation. Relative contraindications include recent bleeding (eg,
gastrointestinal bleeding within 2 weeks, intracranial bleeding
within 3 months), recent trauma, known bleeding disorder, se-
vere thrombocytopenia (platelet count < 75 × 109/L), endocardi-
tis and uncontrolled hypertension.
Risk factors for bleeding include age over 65 years, previous
bleeding, cancer, metastatic cancer, renal failure, liver failure,
MJA 210 (11) ▪ 17 June 2019
anticoagulant therapy.37
Commencing anticoagulation while waiting for test results is
reasonable if the suspicion of DVT is “likely”. Not commencing
anticoagulation while waiting for results is reasonable for pa-
tients at increased risk of bleeding or if the suspicion of DVT
is “unlikely”, provided the results will be available within 24
hours.36
Anticoagulant agents
Options for the initial treatment of VTE include a DOAC (apixa-
ban or rivaroxaban), initial parenteral anticoagulation followed
by a DOAC (dabigatran or edoxaban, because initial parenteral
therapy was administered in the randomised phase 3 trials of da-
bigatran and edoxaban) or initial parenteral anticoagulation over-
lapped by warfarin and continued for at least 5 days and until the
international normalised ratio (INR) is more than 2.0 on two oc-
casions 24 hours apart (evidence level A). The DOACs — compris-
ing the direct thrombin inhibitor dabigatran and the factor Xa
inhibitors rivaroxaban, apixaban and edoxaban — are as effective
as and safer than warfarin (INR, 2.0–3.0) for the treatment of VTE,
whereas betrixaban has not been assessed for VTE treatment and
is indicated only for VTE prophylaxis in hospitalised medical pa-
tients.38,39 Three DOACs — dabigatran, rivaroxaban and apixa-
ban — are approved by the Pharmaceutical Benefits Scheme for
the treatment of VTE. Despite the DOACs being classified col-
lectively, each has a unique molecular structure and they should
therefore be considered as individual anticoagulants (Box 5).40–43
Warfarin is associated with a slightly higher bleeding risk than
DOACs, with an absolute risk increase for major bleeding of

thrombocytopenia, previous stroke, diabetes, anaemia, anti- about 1%, and requires routine coagulation monitoring.36,38,44
platelet therapy, poor anticoagulation control (for vitamin K an-
tagonists), comorbidity and reduced functional capacity, recent Anticoagulant selection
surgery, frequent falls and alcohol misuse. The risk of bleeding
The choice of anticoagulant should consider medical issues such
can be estimated as low, intermediate or high if none, one, or
as efficacy, safety, renal and hepatic function, and concurrent
two or more of these factors are present, respectively.36 Long
medications. In addition, practical issues such as availability, fa-
term concomitant use of non-­steroidal anti-­inflammatory drugs
miliarity of use, patient preference, and cost should be considered.
should be avoided if possible, but short (1–2 weeks) courses of
treatment can be used, for example, in patients with an inflamed DOACs are an ideal first-­line anticoagulant for the treatment of
leg or superimposed superficial phlebitis. For patients who re- VTE in an uncomplicated patient, have advantages over vitamin
518
quire aspirin for cardiovascular prevention, the dose should not K antagonists (Box 6),45 and have few drug–drug interactions
 Narrative review
DVT may be considered provoked if a transient or permanent or
4  Anticoagulants for venous thromboembolism (VTE)36 persistent environmental risk factor is present, or unprovoked if
Phase
no such risk factor is present (Box 3). Risk factors for VTE inform
the risk of recurrent VTE. For example, in patients with VTE
Agent and VTE treatment dose Initial Long term Extended who are treated with 3–6 months of anticoagulation, stopping
Unfractionated heparin 80 IU/ ●
anticoagulation is associated with a one-­year risk of recurrence
kg intravenous bolus, then 18 IU/ of about 1–3% when the initial VTE occurred in the context of
kg per hour a major transient risk factor, about 10% when the event is un-
intravenous infusion, target aPTT provoked, and more than 10% when the event occurs in patients
is hospital-­specific
with active cancer.25 In patients with thrombophilia, factors
Enoxaparin 1.5 mg/kg ● ● ● such as the factor V Leiden and prothrombin gene mutations
subcutaneous daily, or 1.0 mg/kg (cancer) (cancer) are weak determinants of disease recurrence, whereas less com-
subcutaneous twice daily
mon factors such as inherited deficiencies of protein C, protein S
Dalteparin 100 IU/kg subcutane- ● ● ● and antithrombin and the antiphospholipid antibody syndrome
ous twice daily, or for patients with (cancer) (cancer) are stronger predictors of recurrent VTE, for which the THANZ
cancer 200 IU/kg subcutaneous
guidelines suggest extended anticoagulant therapy.29
daily (maximum 18 000 IU/day) for
30 days, 150 IU/kg thereafter Six weeks of anticoagulation are recommended for treatment of
Nadroparin 86 anti-­Xa IU/kg body ● distal DVT caused by a major transient risk factor that is no lon-
weight subcutaneous twice daily ger present (evidence level B). Three months of anticoagulation
Apixaban 10 mg oral twice daily for ● ● ●
are recommended for the treatment of proximal DVT provoked
7 days, then 5 mg twice daily. For by surgery or trauma (evidence level A), proximal DVT provoked
extended treatment, decrease to by a non-­surgical transient risk factor, unprovoked isolated dis-
2.5 mg twice daily tal DVT (evidence level B), and for unprovoked DVT when the
Rivaroxaban 15 mg oral twice daily ● ● ● bleeding risk is high. A minimum of 3 months of anticoagula-
for 21 days, then 20 mg daily. For tion, followed by re-­evaluation of the risk–benefit ratio, is indi-
extended treatment, decrease to cated for unprovoked proximal DVT (evidence level A). At least
10 mg daily
6 months of anticoagulation are recommended for DVT that is
Dabigatran* 150 mg oral twice ● ● provoked by active cancer (evidence level A). Extended anticoag-
daily. Decrease to 110 mg twice ulation is recommended for a second or unprovoked DVT, if risk
daily if age > 75 years or CrCl
factors such as active cancer persist, or for unprovoked proximal
30–49 mL/min
DVT when the bleeding risk is low.44 Patients receiving extended
Warfarin* once daily, oral adminis- ● ● anticoagulation should be followed up at least once per year to
tration; target INR 2.0–3.0 re-­evaluate their individual risk of thrombosis and bleeding,
Aspirin† 100 mg daily (after anti- ● monitor for adverse effects from the anticoagulant, and detect
coagulation ceased) changes that may affect the half-­life of the anticoagulant (eg,
aPTT = activated partial thromboplastin time; CrCl = creatinine clearance; INR = interna- renal impairment). DOACs are preferred over warfarin for long
tional normalised ratio. * Initial parenteral anticoagulation (unfractionated heparin or low term and extended anticoagulation therapy, provided there are
molecular weight heparin) is required for dabigatran for a minimum of 5 days, and for
warfarin until the INR is 2.0–3.0. † For patients with first unprovoked VTE who cannot
no contraindications (evidence level A), but warfarin is a reason-
access or tolerate ongoing anticoagulation but require reduction of thrombosis risk. ◆ able alternative when INR monitoring is feasible and acquisition
costs of DOACs are an issue. After long term treatment of VTE,
extended treatment with low dose apixaban (2.5 mg twice daily)
46–49 or low dose rivaroxaban (10 mg once daily) is effective at reduc-
(Box 7). In patients treated with dabigatran, idarucizumab
ing the risk of recurrent VTE compared with placebo or aspirin,
can reverse anticoagulation in emergency situations (eg, life-­
50 respectively, without increasing the rate of major bleeding.54,55
threatening bleeding, urgent surgery). In patients treated with
rivaroxaban or apixaban, andexanet alfa has been approved in
Inferior vena cava filter
the United States and Europe for reversing the anticoagulant ef-
fect but not yet in Australia. 51 Placement of an inferior vena cava (IVC) filter should be con-
sidered in specific clinical circumstances. Among 2055 patients
DOAC treatment is not recommended in pregnant women and is with acute proximal DVT and a contraindication to anticoagula-
contraindicated in patients with severe renal impairment (creat- tion, IVC filter insertion reduced the risk of subsequent pulmo-
inine clearance [CrCl] < 30 mL/min for edoxaban, rivaroxaban nary embolism by 50% compared with no filter.56 However, IVC
15 mg and 20 mg tablets, and dabigatran; or CrCl < 25 mL/min filters are associated with a 70% increased risk of subsequent
for apixaban; or CrCl < 15 mL/min for rivaroxaban 10 mg tab- DVT when compared with no IVC filter insertion, and carry
MJA 210 (11) ▪ 17 June 2019

lets), severe hepatic impairment (Child–Pugh score C), mechani- unique risks such as filter thrombosis (about 2% of cases), migra-
cal heart valves, and concomitant administration of drug classes tion, and penetration of the wall of the IVC. In a cohort study of
that are strong inhibitors of CYP3A4 and P-­glycoprotein.52,53 126 030 patients with VTE and a contraindication to anticoagula-
When treatment with a DOAC is not appropriate, anticoagula- tion, 30-­day mortality was significantly higher in patients who
tion with intravenous unfractionated heparin, low molecular had an IVC filter inserted compared with no IVC filter (hazard
weight heparin (LMWH) or warfarin are alternatives. ratio [HR], 1.18; 95% CI, 1.13–1.22; P < 0.001).57 IVC filters should
only be considered in patients with an absolute contraindication
Duration of anticoagulation to anticoagulation or selected patients who develop recurrent
The duration of the anticoagulation for DVT depends on the risk pulmonary embolism despite anticoagulation and have signifi-
of recurrence, which is determined by whether the DVT is pro- cant residual DVT (evidence level C).44 Massive pulmonary em-
519
voked by a transient or ongoing risk factor, or unprovoked. A bolism is not an indication for an IVC filter.56,58 The IVC filter
 Narrative review

5  Efficacy of direct oral anticoagulants versus warfarin (international normalised ratio, 2.0–3.0) for symptomatic venous thromboem-
bolism (VTE)

RE- ­COVER40 EINSTEIN-­DVT41 AMPLIFY42 Hokusai-­V TE43

Treatment Dabigatran* (n = 1274) Rivaroxaban* (n = 1731) Apixaban (n = 2691) Edoxaban* (n = 4118)

v warfarin* (n = 1265) v warfarin* (n = 1718) v warfarin* (n = 2704) v warfarin* (n = 4122)

Index event ■ DVT 69% ■ DVT 99% ■ DVT 65% ■ DVT 60%
■ PE 21% ■ PE 1% ■ PE 25% ■ PE 40%
■ PE + DVT 10% ■ PE + DVT 9%

Outcomes HR (95% CI) HR (95% CI) RR (95% CI) HR (95% CI)

† ‡
Primary efficacy 1.10 (0.65–1.84) 0.84 (0.60–1.18) 0.89 (0.70–1.13)‡

Recurrent VTE 0.68 (0.44–1.04)‡

Major bleeding 0.82 (0.45–1.48) 0.65 (0.33–1.30) 0.31 (0.17–0.55)‡ 0.84 (0.59–1.21)

All deaths 0.98 (0.53–1.79) 0.67 (0.44–1.02) 0.79 (0.53–1.19)

AMPLIFY  =  Apixaban for the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis as First-­line Therapy; DVT  =  deep vein thrombosis; EINSTEIN-­DVT  =  Oral Direct
Factor Xa Inhibitor Rivaroxaban in Patients with Acute Symptomatic Deep Vein Thrombosis without Symptomatic Pulmonary Embolism; Hokusai-­V TE  =  Edoxaban versus Warfarin for
the Treatment of Symptomatic Venous Thromboembolism; HR = hazard ratio; RE-­COVER = Efficacy and Safety of Dabigatran Compared with Warfarin for 6-­month Treatment of Acute
Symptomatic Venous Thromboembolism; RR = relative risk. * Initial parenteral anticoagulation (heparin or low molecular weight heparin) was administered. † Recurrent symptomatic VTE
or VTE-­related death. ‡ P < 0.05. ◆

6  Key factors that influence the choice of anticoagulant for venous thromboembolism (VTE)*45

Routine Daily Adverse Reversal

Anticoagulant Indications monitoring injections effects Contraindications† agent Cost

Dabigatran • DVT No No Bleeding,‡ CrCl < 30 mL/min, severe Idarucizumab $$$

• PE dyspepsia ­hepatic impairment, pregnancy,
breastfeeding

Rivaroxaban • DVT No No Bleeding‡ CrCl < 30 mL/min, severe he- $$$

• PE patic impairment, pregnancy,
breastfeeding

Apixaban • DVT No No Bleeding‡ CrCl < 25 mL/min, severe he- $$$

• PE patic impairment, pregnancy,
breastfeeding

Enoxaparin • DVT No Yes Bleeding Heparin-­induced thrombocytope- $$$

• PE nia within previous 100 days
• Cancer-associated
VTE

Dalteparin • DVT No Yes Bleeding Heparin-­induced $$$

• PE thrombocytopenia

Warfarin • DVT Yes No Bleeding, Intracranial haemorrhage, skin Vitamin K, $

• PE intracranial necrosis, pregnancy, breastfeeding prothrombin
haemor- complex
rhage, not concentrate
safe in
pregnancy

Unfractionated • DVT Yes Yes Heparin-­induced Protamine $

heparin • PE thrombocytopenia
• Cancer-associated
VTE

CrCl = creatinine clearance; DVT = deep vein thrombosis; PE = pulmonary embolism. * Patients with acute VTE should be evaluated for treatment with a direct oral anticoagulant (DOAC). In
patients who are eligible for treatment with a DOAC, there is no evidence to recommend one agent over another because the DOACs have not been compared directly. The choice of DOAC
MJA 210 (11) ▪ 17 June 2019

is guided by considering renal function, whether initial parenteral anticoagulation (with dabigatran) is cumbersome, and whether once per day or twice per day dosing is preferred. † Active
bleeding and known hypersensitivity are contraindications for all anticoagulants. ‡ Including upper gastrointestinal tract bleeding. ◆

should be removed preferably within 3 weeks of placement and
when it is safe to resume anticoagulation.
Thrombolysis
Catheter-­directed thrombolysis involves the percutaneous in-
sertion of a catheter and infusion of a thrombolytic — typically
520 recombinant tissue plasminogen activator (tPA) — directly to
the DVT. A randomised trial of anticoagulation plus tPA versus
anticoagulation alone in patients with acute proximal leg DVT
showed no reduction in the risk of PTS and increased bleeding
with dual therapy.59 Patients with recent (<  1  week) extensive,
typically iliofemoral, DVT or with phlegmasia cerulea dolens
and at low bleeding risk were poorly represented in this trial
and may yet benefit from catheter-­directed thrombolysis (evi-
dence level C).60 In contrast to leg DVT, there have been no ran-
domised trials of thrombolysis for treatment of arm DVT.61

7  Direct oral anticoagulant (DOAC) interaction with other medicines
DOAC Contraindicated
46
Rivaroxaban • Antifungals (ketoconazole, itraconazole, voriconazole,
posaconazole)
• HIV protease inhibitors (ritonavir)
Apixaban47 • Antifungals (ketoconazole, itraconazole, voriconazole,
posaconazole)
• HIV protease inhibitors (ritonavir)
• Any other anticoagulant
Dabigatran48 • Antimicrobials (rifampicin, tipranavir)
• Anticonvulsants (carbamazepine, phenytoin,
fosphenytoin)
• Other (dexamethasone, St John’s Wort)
Edoxaban49 • Rifampicin
HIV = human immunodeficiency virus. ◆
Surgical thrombus removal
Surgical removal of DVT does not have a proven role. Some sug-
gest that venous thrombectomy should only be considered in
patients with impending venous gangrene despite optimal an-
ticoagulation and all of the following: catheter-­directed throm-
bolysis not available, iliofemoral DVT, symptoms for less than 7
days, good functional status, life expectancy greater than one
year, and availability of appropriate resources and expertise.36
Compression stockings
Current evidence suggests a beneficial effect of early application
of elastic compression stockings on PTS and residual vein oc-
clusion (evidence level C). In the IDEAL DVT study, compres-
sion stockings worn for at least a minimum of 6 months until
the Villalta score decreased to 4 or less on two consecutive read-
ings, compared with 2 years, were non-­inferior for preventing
PTS in patients with acute proximal DVT (29% v 28%; odds ratio
[OR], 1.06; 95% CI, 0.78–1.44).62 In a pre-­specified substudy of the
IDEAL DVT study, acute compression of the leg within 24 hours
of DVT diagnosis, compared with no compression, was associ-
ated with a decrease in residual vein obstruction (46% v 66%; OR,
0.46; 95%  CI, 0.27–0.80) and PTS (46% v 54%; OR, 0.65; 95%  CI,
0.46–0.92).63
Secondary prevention of venous thromboembolism
Aspirin 100 mg daily is reasonable to decrease the risk of recur-
rent VTE in patients who have completed anticoagulation treat-
ment for a first unprovoked DVT or pulmonary embolism, and
in whom ongoing anticoagulation is not appropriate or cannot
be accessed.64 Since the introduction of DOACs, new second-
ary prevention strategies have been tested. In patients with VTE
who had completed 6–12 months of anticoagulant therapy, and
in whom there was clinical equipoise regarding the continua-
tion or cessation of anticoagulant therapy, extended anticoagula-
tion with low dose apixaban 2.5 mg twice daily for a further 12
months was more effective than placebo in reducing recurrent
VTE or death from any cause (relative risk [RR], 0.33; 95%  CI,
0.22–0.48) without increasing major bleeding (RR, 0.49; 95% CI,
Narrative review
Caution
• Antifungals (fluconazole)
• Antibiotics (clarithromycin, erythromycin, rifampicin)
• Antiarrhythmics (amiodarone, quinidine, diltiazem, verapamil)
• Anticonvulsants (phenytoin, carbamazepine, phenobarbitone)
• Other (cyclosporine, St John’s Wort)
• Co-administration with other anticoagulants or antiplatelets
• Antibiotics (clarithromycin, rifampicin)
• Anticonvulsants (phenytoin, carbamazepine, phenobarbitone)
• Antiarrhythmics (diltiazem, amiodarone, quinidine, verapamil)
• Non-steroidal anti-inflammatory drugs (naproxen)
• Co-administration with other anticoagulants and antiplatelets
• Antifungals (ketoconazole)
• Antibiotics (erythromycin)
• Antiarrhythmics (quinidine, dronedarone)
• HIV protease inhibitors (darunavir/ritonavir, lopinavir/ritonavir)
• Non-steroidal anti-inflammatory drugs (naproxen)
• Other (cyclosporine)
• Co-administration with other anticoagulants and antiplatelets
0.09–2.64).54 In another similar population, extended antico-
agulation with rivaroxaban was more effective than aspirin in
reducing recurrent VTE (HR, 0.34; 95% CI, 0.20–0.59, for 20 mg
daily dose; HR, 0.26; 95%  CI, 0.14–0.47, for 10  mg daily dose v
aspirin), without a significant increase in bleeding rates (major
bleeding 0.5% with rivaroxaban 20  mg, 0.4% with rivaroxaban
10 mg, and 0.3% with aspirin 100 mg daily).55
Special circumstances affecting the diagnosis and
management of deep vein thrombosis
Pregnancy
Pregnant women may not be assessed accurately using the Wells
rule for DVT because the rule was derived from a non-­pregnant
population. The LEFt rule is an alternative clinical prediction
rule that assigns one point each for symptoms in the left leg, calf
circumference difference of 2 cm or more, and first trimester of
pregnancy.65 A LEFt score of zero points is accurate to rule out
DVT in pregnant women.66 D-­dimer level is less likely to rule out
DVT in pregnancy because it steadily increases until delivery;
therefore, reports conflict over whether to perform this test for
suspected VTE in pregnancy.18,66 When DVT is confirmed, the
most appropriate anticoagulation is LMWH (evidence level A).
Warfarin use during pregnancy is associated with an increased
risk for fetal embryopathy, especially when used during weeks
6–12 of gestation.67 DOACs have been used in pregnancy, but
experience is limited.68 As DOACs are small molecules that cross
the placenta, there is potential for adverse effects on the fetus.
MJA 210 (11) ▪ 17 June 2019
Cancer
Active cancer may be associated with an increased D-­dimer level
even if DVT is not present, which reduces the negative predic-
tive value for DVT.18 Previously, LMWH has been recommended
for treatment of DVT for patients with cancer because, compared
with warfarin, the rate of recurrent VTE is lower and the rate
of bleeding is similar.69 The optimal duration of anticoagula-
tion for cancer-­associated VTE has not been formally assessed
beyond 6 months. Continuing anticoagulation for longer than 6 521
months is indicated if the cancer is still active or treatment with
 Narrative review
chemotherapy, radiotherapy or hormonal therapy is ongoing.27,70
Two DOACs have recently been compared with LMWH for cancer-­
related VTE. Edoxaban (after 5 days of initial LMWH), compared
with LMWH (dalteparin), was non-­inferior for the composite out-
come of recurrent VTE or major bleeding. The rate of recurrent
VTE was not different (7.9% v 11.3%; HR, 0.71; 95% CI, 0.48–1.06),
but the risk of major bleeding was higher with edoxaban (6.9%
v 4.0%; HR, 1.77; 95% CI, 1.03–3.04) and there was no difference
in mortality.71 Rivaroxaban (no initial LMWH), compared with
dalteparin, decreased the rate of recurrent VTE (HR, 0.43; 95% CI,
0.19–0.99) and increased the risk of clinically relevant non-­major
bleeding (HR, 3.76; 95% CI, 1.63–8.69), but the risk of major bleed-
ing was not significantly different (HR, 1.83; 95% CI, 0.68–4.96).72
In both trials, the increased rate of bleeding with DOACs was
mainly due to the higher rate of upper gastrointestinal bleeding
in patients enrolled with gastrointestinal cancer. These data sup-
port rivaroxaban and edoxaban as effective oral treatment op-
tions for patients with VTE and cancer (evidence level B).
Distal deep vein thrombosis
Isolated distal (calf) DVTs have a lower risk of extension than
proximal DVTs and do not always require anticoagulation.
About 15% of isolated distal DVTs will extend to the proximal
veins if not treated, usually in less than 2 weeks.73 Treatment
with anticoagulation for 3 months may be considered for patients
with distal DVT who have a significant symptom burden, or if
risk factors for extension are present (eg, thrombosis > 5 cm in
length, > 7 mm maximum diameter, involving multiple veins),
the DVT is unprovoked, there is a history of active cancer or pre-
vious VTE, or the patient is currently admitted to hospital. If the
patient is asymptomatic and does not initially receive anticoagu-
lation, it is suggested to repeat the CUS after 1–2 weeks to detect
possible proximal extension.73
Recurrent deep vein thrombosis
Recurrent DVT is more difficult to diagnose than first DVT be-
cause the features of the initial episode of DVT may persist on
CUS.74 Diagnosis of recurrent DVT may be assisted by compar-
ing the CUS with a previous one at the end of treatment of the
first DVT. Hence, repeating the CUS at the end of anticoagula-
tion, although not performed routinely,24 can be valuable in
patients with high risk of recurrence (eg, unprovoked proximal
DVT). When VTE recurs during anticoagulation treatment, the
patient should be evaluated for suboptimal anticoagulation ther-
apy (eg, incorrect dose, poor adherence) and the emergence of
conditions that increase the risk of recurrent VTE (eg, cancer).75
Antiphospholipid syndrome
Patients with antiphospholipid syndrome should be anticoagu-
lated with warfarin.31 In high risk patients with antiphospho-
lipid syndrome, rivaroxaban treatment was associated with no
benefit and increased risk compared with warfarin (evidence
level C).76 Further studies are needed to assess the safety of
DOACs in selected, lower risk patients with antiphospholipid
syndrome.
Superficial vein thrombosis
Superficial vein thrombosis manifests as thrombosis of a super-
ficial venous system and is associated with a low incidence of
proximal DVT and pulmonary embolism. Anticoagulation with
a prophylactic dose of LMWH or fondaparinux for 45 days is
recommended in patients with leg superficial vein thrombo-
sis greater than 5 cm in length, severe symptoms, involvement
of the greater saphenous vein, history of VTE or superficial
vein thrombosis, active cancer, and recent surgery (evidence
level C). Patients with superficial vein thrombosis above the
knee should have a CUS to investigate for DVT. Non-­steroidal
anti-­inflammatories can alleviate pain in patients who are not
anticoagulated.36
Conclusion
The diagnosis of DVT requires a high index of suspicion because
symptoms and signs are often non-­ specific. Anticoagulation
continues to be the cornerstone of therapy. The optimal antico-
agulant and duration of therapy are determined by the clinical
assessment.
Competing interests: No relevant disclosures.
Provenance: Commissioned; externally peer reviewed. ■
© 2019 AMPCo Pty Ltd

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